Impact of protective IL-2 allelic variants on CD4+ Foxp3+ regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice.
Type I diabetes (T1D) susceptibility is inherited through multiple insulin-dependent diabetes (Idd) genes. NOD.B6 Idd3 congenic mice, introgressed with an Idd3 allele from T1D-resistant C57BL/6 mice (Idd3(B6)), show a marked resistance to T1D compared with control NOD mice. The protective function of the Idd3 locus is confined to the Il2 gene, whose expression is critical for naturally occurring CD4(+)Foxp3(+) regulatory T (nT(reg)) cell development and function. In this study, we asked whether Idd3(B6) protective alleles in the NOD mouse model confer T1D resistance by promoting the cellular frequency, function, or homeostasis of nT(reg) cells in vivo. We show that resistance to T1D in NOD.B6 Idd3 congenic mice correlates with increased levels of IL-2 mRNA and protein production in Ag-activated diabetogenic CD4(+) T cells. We also observe that protective IL2 allelic variants (Idd3(B6) resistance allele) also favor the expansion and suppressive functions of CD4(+)Foxp3(+) nT(reg) cells in vitro, as well as restrain the proliferation, IL-17 production, and pathogenicity of diabetogenic CD4(+) T cells in vivo more efficiently than control do nT(reg) cells. Lastly, the resistance to T1D in Idd3 congenic mice does not correlate with an augmented systemic frequency of CD4(+)Foxp3(+) nT(reg) cells but more so with the ability of protective IL2 allelic variants to promote the expansion of CD4(+)Foxp3(+) nT(reg) cells directly in the target organ undergoing autoimmune attack. Thus, protective, IL2 allelic variants impinge the development of organ-specific autoimmunity by bolstering the IL-2 producing capacity of self-reactive CD4(+) T cells and, in turn, favor the function and homeostasis of CD4(+)Foxp3(+) nT(reg) cells in vivo.
Sgouroudis
Evridiki
E
Department of Microbiology and Immunology, and McGill Center for the Study of Host Resistance, McGill University, Montreal, Québec, Canada.
Albanese
Alexandre
A
Piccirillo
Ciriaco A
CA
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2